# Androgen signaling and sterol metabolism in metastatic prostate cancer: Functional and therapeutic implication

> **NIH NIH R15** · CLEVELAND STATE UNIVERSITY · 2021 · $412,416

## Abstract

Abstract
Prostate cancer (PCa) is the most commonly diagnosed cancer in men and the second leading
cause of cancer-related deaths in the USA. Relapsed androgen signaling and intratumoral sterol
biosynthesis are hallmarks of castration-resistant PCa (CRPC). PCa growth and proliferation
depend on androgen signaling by the Androgen Receptor (AR). Targeting the androgen
synthesis pathways and transactivation function of AR is a primary therapeutic approach to treat
PCa. The progression of PCa from castration-sensitive to the castration-resistant stage (CRPC)
depends on the failure of androgen signaling antagonists and the dysregulation of AR-centric
molecular mechanisms in a high percentage of patients. Recent studies show that microRNAs
(miRNAs) exert post-transcriptional regulation of gene expression by targeting oncogenes and
performing tumor-suppressive functions in various cancers, including PCa. Scientific premise:
The fundamental discovery motivating the proposed study is that miR-149-5p targets the
expression of two major transcription factors AR and sterol regulatory element-binding
transcription factor 1 (SREBF1), both are druggable targets and are implicated in CRPC. Our
central hypothesis entails that miR-149-5p post-transcriptionally downregulates AR and
SREBF1, and inactivation of miR-149-5p expression during the prostate carcinogenesis leads to
the upregulation of androgen signaling and sterol biosynthesis, which promotes CRPC. We will
test our hypothesis by pursuing three integrated Specific Aims. In aim 1 we will test miR-149-5p
anti-proliferation and anti-oncogenic function in PCa cells, in Aim 2, we will define molecular
mechanisms which negatively affects the maturation of miR-149-5p and in the aim 3, we will test
the therapeutic and prognostic value of miR-149-5p. Significance: The study will provide a
tumor-suppressor role of miR-149-5p in CRPC. The innovative research approaches the
disease from a novel miRNA-mediated control of the androgen signaling and intratumoral sterol
biosynthesis pathways in particular testosterone metabolism by directly co-targeting AR and
SREBF1, and both are druggable targets in CRPC. This study has the potential to test for the
first time co-targeting of primary PCa promoting transcription factors and a new paradigm for
improved patient therapies by identifying the significant key regulators of androgen signaling
and sterol biosynthesis pathways.

## Key facts

- **NIH application ID:** 10201013
- **Project number:** 1R15CA252997-01A1
- **Recipient organization:** CLEVELAND STATE UNIVERSITY
- **Principal Investigator:** Girish C Shukla
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $412,416
- **Award type:** 1
- **Project period:** 2021-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10201013

## Citation

> US National Institutes of Health, RePORTER application 10201013, Androgen signaling and sterol metabolism in metastatic prostate cancer: Functional and therapeutic implication (1R15CA252997-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10201013. Licensed CC0.

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